Substituted benzimidazoles for neurofibromatosis

Abstract

The present invention relates to the use of BENZIMIDAZOLE DERIVATIVES for the preparation of a drug for the treatment of neurofibromatosis.

1 . A method of treating or preventing a condition caused by neurofibromatosis, comprising administering a benzimidazole derivative of formula (I): 
       
         
           
           
               
               
           
         
         wherein,
 each R 1  is independently selected from hydroxy, halo, C 1-6  alkyl, C 1-4  alkoxy, (C 1-6  alkyl)sulfanyl, (C 1-6  alkyl)sulfonyl, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl; 
 R 2  is C 1-6  alkyl or halo(C 1-6  alkyl); 
 each R 3  is independently selected from halo, C 1-6  alkyl, and C 1-6  alkoxy; 
 each R 4  is independently selected from hydroxy, C 1-6  alkyl, C 1-6  alkoxy, halo, carboxyl, (C 1-6  alkoxy)carbonyl, aminocarbonyl, C 1-6  alkylaminocarbonyl, carbonitrile, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, phenyl and heteroaryl; 
 wherein R 1 , R 2 , R 3  and R 4  may be optionally substituted with one or more substituents independently selected from hydroxy, halo, C 1-6  alkyl, halo(C 1-6  alkyl), C 1-6  alkoxy and halo(C 1-6  alkoxy); 
 a is 1, 2, 3, 4, or 5; 
 b is 0, 1, 2, or 3; and 
 c is 1 or 2; 
 
         or a tautomer or stereoisomer, thereof or a pharmaceutically acceptable salt of the compound, tautomer or stereoisomer. 
       
     
     
         2 . A method according to  claim 1 , where the condition caused by neurofibromatosis is selected from non-cancerous, benign brain tumors, meningiomas, schwannomas, craniopharyngiomas, dermoids, epidermoids, hemangioblastomas, choroid plexus papillomas and pineal region tumors. 
     
     
         3 . A method according to  claim 1 , where the neurofibromatosis is selected from neurofibromatosis type 1 or type 2. 
     
     
         4 . A method according to  claim 1 , where the compound of formula (I) is 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl] benzamide of formula (II): 
       
         
           
           
               
               
           
         
         or a tautomer of the compound of formula (II) or a pharmaceutically acceptable salt of the tautomer having the formula (III): 
       
       
         
           
           
               
               
           
         
       
     
     
         5 - 10 . (canceled) 
     
     
         11 . A method for treating mammals, including humans, suffering from non-cancerous, benign brain tumors comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (II): 
       
         
           
           
               
               
           
         
         or a tautomer of the compound of formula (II) or a pharmaceutically acceptable salt of the tautomer having the formula (III): 
       
       
         
           
           
               
               
           
         
       
     
     
         12 . A pharmaceutical preparation for the treatment of non-cancerous, benign brain tumors, comprising a compound of formula (II): 
       
         
           
           
               
               
           
         
         or a tautomer of the compound of formula (II) or a pharmaceutically acceptable salt of the tautomer having the formula (III):